Smoking and cancer‐related gene expression in bronchial epithelium and non‐small‐cell lung cancers

Abstract

Tobacco smoking is the leading cause of lung cancer worldwide. Gene expression in surgically resected and microdissected samples of non-small-cell lung cancers (18 squamous cell carcinomas and nine adenocarcinomas), matched normal bronchial epithelium, and peripheral lung tissue from both smokers (n = 22) and non-smokers (n = 5) was studied using the Affymetrix U133A array. A subset of 15 differentially regulated genes was validated by real-time PCR or immunohistochemistry. Hierarchical cluster analysis clearly distinguished between benign and malignant tissue and between squamous cell carcinomas and adenocarcinomas. The bronchial epithelium and adenocarcinomas could be divided into the two subgroups of smokers and non-smokers. By comparison of the gene expression profiles in the bronchial epithelium of non-smokers, smokers, and matched cancer tissues, it was possible to identify a signature of 23 differentially expressed genes, which might reflect early cigarette smoke-induced and cancer-relevant molecular lesions in the central bronchial epithelium of smokers. Ten of these genes are involved in xenobiotic metabolism and redox stress (eg AKR1B10, AKR1C1, and MT1K). One gene is a tumour suppressor gene (HLF); two genes act as oncogenes (FGFR3 and LMO3); two genes are involved in matrix degradation (MMP12 and PTHLH); three genes are related to cell differentiation (SPRR1B, RTN1, and MUC7); and five genes have not been well characterized to date. By comparison of the tobacco-exposed peripheral alveolar lung tissue of smokers with non-smokers and with adenocarcinomas from smokers, it was possible to identify a signature of 27 other differentially expressed genes. These genes are involved in the metabolism of xenobiotics (eg GPX2 and FMO3) and may represent cigarette smoke-induced, cancer-related molecular targets that may be utilized to identify smokers with increased risk for lung cancer.

Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

“…GSH peroxidase 2 mRNA was also found to be more frequently expressed in tumour as compared to normal breast tissue; this enzyme can protect cells from free radicals and also regulate proliferation and apoptosis through redox signalling [24] and thus its increased expression may confer a survival advantage to tumour cells. Expression of GSH peroxidase 2 has been established in breast tissue [25] and increased expression of this enzyme has recently been reported in lung adenocarcinomas and in normal alveolar epithelium from smokers as compared to normal lung tissue from non-smokers [26]. Differential mRNA expression of ARNT2 was one of the major findings in our study, with expression in tumour tissue being much more prevalent than in normal tissue specimens and significantly correlating with better prognosis.…”

Genomics of Smoking Exposure and Cessation: Lessons for Cancer Prevention and Treatment

“…Zhang and colleagues provide further in vivo evidence that many of these genes are down-regulated in persons who reported quitting smoking at least 1 year before the assessment (CYP1B1, AKR1C1, AKR1C2, AKR1B10, and ALDH3A1). Many of these same genes were previously shown to be overexpressed in oral cancer cells exposed to tobacco smoke condensate (8), in bronchial epithelial cells of smokers, and in patients' non-small cell lung carcinoma cells (9,10). The effects are also consistent with the effects of smoking on the airway transcriptome (11,12).…”

Evidence for the aldo-keto reductase pathway of polycyclic aromatic trans -dihydrodiol activation in human lung A549 cells

“…Clinical and epidemiological studies support the concept that AKR isoforms, which lead to oxidative DNA damage, can contribute to the initiation of lung cancer (21,22). Moreover, AKR expression in human oral squamous cell carcinoma has been observed after areca-quid chewing in combination with smoking (40).…”